Search Results

You are looking at 1 - 4 of 4 items for

  • Author: A. J. SMITH x
  • Refine by access: Content accessible to me x
Clear All Modify Search
Vicki E Smith School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TH, UK

Search for other papers by Vicki E Smith in
Google Scholar
PubMed
Close
,
Jayne A Franklyn School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TH, UK

Search for other papers by Jayne A Franklyn in
Google Scholar
PubMed
Close
, and
Christopher J McCabe School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TH, UK

Search for other papers by Christopher J McCabe in
Google Scholar
PubMed
Close

Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.

Free access
J T Smith School of Human Sciences, The University of Western Australia, Perth, Western Australia, Australia

Search for other papers by J T Smith in
Google Scholar
PubMed
Close
,
A Roseweir Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, UK
Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow Glasgow, UK

Search for other papers by A Roseweir in
Google Scholar
PubMed
Close
,
M Millar Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

Search for other papers by M Millar in
Google Scholar
PubMed
Close
,
I J Clarke Department of Physiology, Monash University, Clayton, Victoria, Australia

Search for other papers by I J Clarke in
Google Scholar
PubMed
Close
, and
R P Millar Centre for Neuroendocrinology, Department of Immunology and Physiology, University of Pretoria, Pretoria, South Africa
Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

Search for other papers by R P Millar in
Google Scholar
PubMed
Close

Kisspeptin signalling is indispensable for fertility, stimulating gonadotropin-releasing hormone (GnRH) secretion and mediating gonadal steroid feedback on GnRH neurons. Moreover, kisspeptin neurons have been implicated in other non-reproductive neuroendocrine roles. Kisspeptin appears to also regulate growth hormone secretion but much of the data appear contradictory. We sought to clarify a potential role of kisspeptin in growth hormone (GH) regulation by examining the effect of kisspeptin antagonists on GH secretion in ewes under various physiological conditions. Our data show clear and robust increases in GH secretion following lateral ventricle or third ventricle infusion of kisspeptin antagonists p-234 and p-271 in either ovariectomized or anestrous ewes. Central infusion of kisspeptin-10 had no effect on GH secretion. To determine the level at which kisspeptin may influence GH secretion, we examined expression of the cognate kisspeptin receptor, GPR54, in pituitary cells and showed by immunocytochemistry that the majority of somatotropes express GPR54 while expression was largely negative in other pituitary cells. Overall, we have demonstrated that blocking kisspeptin signalling by antagonists stimulates GH secretion in ewes and that this is likely mediated by inhibiting endogenous kisspeptin activation of GPR54 expressed on somatotropes. The findings suggest that endogenous kisspeptin inhibits GH secretion through GPR54 expressed on somatotropes.

Free access
K L Davies Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Search for other papers by K L Davies in
Google Scholar
PubMed
Close
,
E J Camm Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia

Search for other papers by E J Camm in
Google Scholar
PubMed
Close
,
D J Smith Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Search for other papers by D J Smith in
Google Scholar
PubMed
Close
,
O R Vaughan Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Institute for Women’s Health, University College London, London, UK

Search for other papers by O R Vaughan in
Google Scholar
PubMed
Close
,
A J Forhead Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

Search for other papers by A J Forhead in
Google Scholar
PubMed
Close
,
A J Murray Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Search for other papers by A J Murray in
Google Scholar
PubMed
Close
, and
A L Fowden Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

Search for other papers by A L Fowden in
Google Scholar
PubMed
Close

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

Open access
K L Davies Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK

Search for other papers by K L Davies in
Google Scholar
PubMed
Close
,
J Miles Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK

Search for other papers by J Miles in
Google Scholar
PubMed
Close
,
E J Camm Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia

Search for other papers by E J Camm in
Google Scholar
PubMed
Close
,
D J Smith Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK

Search for other papers by D J Smith in
Google Scholar
PubMed
Close
,
P Barker MRC Metabolic Diseases Unit, Mouse Biochemistry Laboratory, Cambridge Biomedical Campus, Cambridge, UK

Search for other papers by P Barker in
Google Scholar
PubMed
Close
,
K Taylor Endocrine Laboratory, Blood Sciences, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge, UK

Search for other papers by K Taylor in
Google Scholar
PubMed
Close
,
A J Forhead Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

Search for other papers by A J Forhead in
Google Scholar
PubMed
Close
, and
A L Fowden Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, UK

Search for other papers by A L Fowden in
Google Scholar
PubMed
Close

Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose–insulin dynamics and pituitary–adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1–2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic–euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary–adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.

Open access